A platform of cytoskeletalcomponents regulates the morphology of neurons. Along these lines, proteinsthat associates with important cytoskeletal segments such as microtubules canalter directly both the morphology and physiology of neurons. Tau is amicrotubule associated protein (MAP) that behaves differently from other typesof proteins, its unfolded formation determines specificity in the function oftau. Tau settles and stabilises neuronal microtubules under ordinaryphysiological conditions, acting as blocks of Legos constantly securing themorphology of neurons.
However, under certain pathological circumstances, tauundergo modifications that forms abnormal aggregates in neurofibrillary whichare harmful to neurons. This procedure happens in various neurological issuesknown as tauopathy, the most regularly perceived tauopathy is Alzheimer’sdisease. The motivation behind this audit is to characterise the role of tauprotein under normal physiological condition in neuron and how tau contributesto the development of Alzheimer’s disease.Microtubules regulates activitiesfrom cell morphology to cytoskeletal organisation, the crucial role ofmicrotubules requires a vast amount of MAP for regulation purposes (MaccioniRB, Cambiazo V,2004). Tau, collectively known as MAP, is one of many thatmodulates the association and interaction of microtubules, thence indirectlymaintaining normal cell function. From molecules of tubulin heterodimers to a cylindricalmicrotubule that consists of ?and ? tubulin, the dynamics involved are purely supportedby MAP (Pryer NK.et al,2006). Tau contains two different way of regulating axonalmicrotubule stability, isoform and differential phosphorylation.
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The humanbrain contains six isoforms of tau that are uniquely generated by tau gene alternativesplicing (Pamela McMillan. Et al ,2008). The isoforms are composed of eitherthree or four tandem repeats with two projection terminal inserts on both sides,C and N, responsible for interacting with microtubule(Pamela McMillan. Et al,2008). A study executed by Maxime Derisbourg analyse the role of N-terminalinserts in the stabilisation of microtubule (Derisbourg M. et al, 2015). Two specificN-terminal inserts were truncated at Met11 and Gln24 respectively, biochemicalresults show Gln-24 has the ability to bind and stabilise microtubules (DerisbourgM.
et al, 2015). This suggests the importance of isoforms in the role of directmicrotubule stabilisation by tau. Further, tandem repeats of isoforms act as’jaws’, flanking the turn edges of tubulin to promote bundle formation ofmicrotubules, enhancing the efficiency of microtubule nucleation and elongation(Gustke N.
et al, 2003), ultimately making suitable adjustments on microtubuledynamics. Differential phosphorylation of tau is another predominant mechanism thatorchestrates axonal microtubule stability. Addition of phosphate by proteinkinase alters the molecular shape of tau (Fatma J. Ekinci and Thomas B. Shea,2000), in turn possibility affecting the assembly of microtubules andthreatening stability. Lund ET respectively reported human tau phosphorylatedby protein kinase II actually promotes microtubule disassembly bydepolymerising tubulin structures, resulting in catastrophic disconnectionsbetween tau and microtubule (Lund ET.et al , 2001).
Furthermore, an increase inlevels of tau phosphorylation at Thr231 might result in increase of tau-tauinteraction, involving in neurodegenerative disease including Alzheimer’s (AkikoMaruko-Otake. Et al,2016) (more will be discussed upon in latter part). It isof critical importance that that amount of kinase and phosphatase are wellmaintained so hyperphosphorylation will not result and tau could functionoptimally.
Recent article by Liu Fung, highlights tau dephosphorylation byprotein phosphate 5 can reduce the effect of abnormal hyperphosphorylation in Alzheimer’s(LiuF. et al , 2005), suggesting how essential is tau in maintaining stablemicrotubule.Specific areas of tau protein bindsto ? and ? tubulin of microtubules (Auréliane Elie. Et al,2015), likewisetubulin molecules bind to motor kinesin and dynein. In fact apart fromstabilisation, tau protein indirectly takes part in axonal transport,interfering with motor proteins. Evidences conducted by Dixit R shows that tau actuallyrelates to the light chain of motor protein kinesin-1 and the relationshipentirely depends on the phosphorylation state of tau (Dixit R.
et al, 2008). Forinstance, hyperphosphorylation can lead to the disassociation of tau frommicrotubule, losing tau function in axonal transport (Lund ET.et al , 2001),progressively leading to Alzheimer’s. This solidifies the importance of differentialphosphorylation of tau in modulating axonal transports by regulating thebinding to kinesin-1(Dixit R.et al, 2008). Findings by numerous gene knockoutexperiments support a new role of Tau protein in addition to its establishedrole in maintaining the stability of microtubule, tau is actually required forthe outgrowth of neurites.
Knock-out mice with the loss of tau function wastested against wild type mice and neurite extension rate was measuredrespectively under different circumstances (Liu CW. Et al , 2000). The knockout mice turns out to have a significantly smaller neurite extension rate byapproximately two folds when comparing to a wild type mice with normal tau function(Liu CW. Et al, 2000). The redefined (knockout) mice demonstrated a postponedneuronal development accompanied by the decrease in the neurite extension rate,indicating the cooperative function of tau underlies the specific role of tau inregulating the outgrowth of neurites. This implies hyperphosphorylation of taucan lead to axonal degradation when tau stops stabilising microtubules, movingone step closer to contracting Alzheimer’s (Liu F.
et al, 2005). Lastly, tau represents linker thatconnects two cytoskeletal components together, acting as a bridge that crosslinks filament networks and axonal microtubules via tubulin binding sites. Forinstance, tau induces the co-alignment of growing microtubules along filamentsbundles, promoting guided polymerisation of microtubules and developing apattern of co-organising stability (Stuart Feinstein, Nichole Lapointe,2017).
Studies shown C- terminal part of tau has the ability more thansufficient to physically link microtubule and actin filaments together,stabilising microtubule(Stuart Feinstein, Nichole Lapointe, 2017), alsothe proportion of microtubule associated with actin filaments greatly increasesunder the influence of tau when comparing to microtubule-actin surface networkunder fascin environment(Elie A. et al, 2015). An increase in the phosphatelevel of tau can threaten the co –organising stability of microtubule, reducingmicrotubule networks, developing Alzheimer’s eventually. The graph (Elie A. et al, 2015) on the side sates how thecoordination of actin and microtubule by tau improves the formation microtubulenetwork and essentially perform a critical role in the context of neurones.
For the most part tau worksperfectly in neurons, maintaining the stability of microtubules and enabling aspeedy transport of axonal motor proteins. Furthermore, supporting theoutgrowth of neurites and crosslinking actin networks with microtubules.However, dysfunction of tau was actually found to be pathological hallmark of Alzheimer’sdisease, abnormally phosphorylated tau aggregates in the neurofibrillarytangles of the brain (Goran Šimi?. Et al,2016). In an actively function neuron,microtubules forms and breaks up all the time. Tau’s binding capacity onmicrotubule is always being adjusted by the addition or removal phosphate.Enzymes including kinase add phosphate on tau protein, deliberately weakeningtau’s grip (Philip J Dolan and Gail VW Johnson, 2010). Different enzyme calledphosphateses catalysts in a vice versa reaction, de-phosphorylating tau toincrease tau’s capacity to grip (Liu F.
et al , 2005). Alzheimer’s happen when thephosphorylation process goes out of control and tau protein becomes hyperphosphorylated.The brains of Alzheimer’s contain roughly 9 mol of phosphate while normalbrains contain only 2 mol (E. MandelkowJ.
Et al , 1994). The staggeringincrease of phosphate changes tau from a state of natively unfolded protein toaggregates that ultimately forms neurofibrillary tangles in neurons. These typeof neurofibrillary tangles afflicts directly on a normal person’s brain, sodepending on the degree of tau compromising into neurofibrillary tangle,actually correlates with the severity of dementia in a patient (Shaheen ELakhan, 2017).
It is also equally fair to mention hyperphosphorylation canresult in the disassembly of microtubules and the reason behind the imbalanceof phosphate level is triggered by ?-amyloid peptide in Alzheimer’s, which inturn develops senile plaques contributing to the aggregates in Alzheimer’s (PCras.et al , 2001). Studies demonstrated there are atleast 39 identified phosphorylated sites in the tau molecule that associates tothe brain of Alzheimer’s patient when phosphorylation-dependent monoclonalantibodies are introduced to the sample (Diane P. Hanger.et al, 2007). Phosphatedependent Tau is actually the ‘culprit’ that is responsible for the developmentof inclusions in Alzheimer’s, acting as a piece of domino that triggers a wholeseries of downstream adverse effects.
It is widely recognised that tauhas the ability to support microtubules under most circumstances examplesinclude microtubule stability and axonal transport. However, under pathologicalconditions, initial formations of fibrillary tangles from tau proteins promotesthe onset and evolution of Alzheimer’s.